Circuitry for Associative Plasticity in the Amygdala Involves Endocannabinoid Signaling

Endocannabinoids are crucial for the extinction of aversive memories, a process that considerably involves the amygdala. Here, we show that low-frequency stimulation of afferents in the lateral amygdala with 100 pulses at 1 Hz releases endocannabinoids postsynaptically from neurons of the basolateral amygdala of mice in vitro and thereby induces a long-term depression of inhibitory GABAergic synaptic transmission (LTDi) via a presynaptic mechanism. Lowering inhibitory synaptic transmission significantly increases the amplitude of excitatory synaptic currents in principal neurons of the central nucleus, which is the main output site of the amygdala. LTDi involves a selective mGluR1 (metabotropic glutamate receptor 1)-mediated calcium-independent mechanism and the activation of the adenylyl cyclase-protein kinase A pathway. LTDi is abolished by the cannabinoid type 1 (CB1) receptor antagonist SR141716A and cannot be evoked in CB1 receptor-deficient animals. LTDi is significantly enhanced in mice lacking the anandamide-degrading enzyme fatty acid amide hydrolase. The present findings show for the first time that mGluR activation induces a retrograde endocannabinoid signaling via activation of the adenylyl cyclase-protein kinase A pathway and the release of anandamide. Furthermore, the results indicate that anandamide decreases the activity of inhibitory interneurons in the amygdala. This disinhibition increases the activity of common output neurons and could provide a prerequisite for extinction by formation of new memory.

• Publication year

  2004

• Venue

  Journal of Neuroscience

• Publication date

  2004-11-03

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1523/JNEUROSCI.2134-04.2004PMID 15525780PMCID PMC6730232
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Emotion circuits in the brain.

  2009cited by this paper
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  2003cited by this paper
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• Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors.

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  1999cited by this paper
• Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action.

  1998cited by this paper
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  1998cited by this paper
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  1998cited by this paper
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  1994cited by this paper
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